1. Volume 145, Issue 5, Pages 1035-1044.e5 (November 2013)
Effects of Ribavirin Dose Reduction vs Erythropoietin for Boceprevir-Related Anemia in Patients With Chronic Hepatitis C Virus Genotype 1 Infection—A Randomized Trial 
Fred Poordad, Eric Lawitz, K. Rajender Reddy, Nezam H. Afdhal, Christophe Hézode, Stefan Zeuzem, Samuel S. Lee, Jose Luis Calleja, Robert S. Brown, Antonio Craxi, Heiner Wedemeyer, Lisa Nyberg, David R. Nelson, Lorenzo Rossaro, Luis Balart, Timothy R. Morgan, Bruce R. Bacon, Steven L. Flamm, Kris V. Kowdley, Weiping Deng, Kenneth J. Koury, Lisa D. Pedicone, Frank J. Dutko, Margaret H. Burroughs, Katia Alves, Janice Wahl, Clifford A. Brass, Janice K. Albrecht, Mark S. Sulkowski 
Gastroenterology 
Volume 145, Issue 5, Pages e5 (November 2013)
DOI: /j.gastro
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2. Figure 1
End of treatment response, SVR rates, and relapse rate. End of treatment response, SVR rates, and relapse rates for the 2 anemia-management strategies (A) and SVR rates by HCV RNA levels at start of primary anemia management (B). If a patient had undetectable HCV RNA at 12 weeks after the end of treatment, but had missing HCV RNA values at and after 24 weeks after the end of treatment, this was considered an SVR. The stratum-adjusted difference adjusted for stratification factors and protocol cohort for the SVR values for EPO use (70.9%) vs RBV dosage reduction (71.5%) in panel A was −0.7% (95% CI: −8.6 to 7.2).
Gastroenterology  , e5DOI: ( /j.gastro )
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3. Figure 2
Rates of virologic responses among patients in the RBV dosage-reduction arm according to lowest RBV dosage, number of steps of RBV dosage reduction, and percent of total RBV dosage received. The SVR rates are shown for several subgroups in the RBV dosage-reduction arm. (A) The lowest RBV dosage was defined as the lowest daily dosage of RBV (mg/d) received for at least 14 days during the treatment period based on information in patient diaries. A lowest RBV dosage of 0 mg/d refers to patients who had many RBV dosage reductions and/or interrupted RBV temporarily for at least 14 days. (B) An RBV dosage-reduction step was defined as a decrease of 200 mg/d for ≥3 days based on information in patient diaries. (C, D) Percent of total RBV dosage received was calculated as the total milligrams of RBV actually received by the patient during the entire treatment period divided by the total milligrams of RBV assigned by the protocol for the entire treatment period. Results are shown for the overall population (C), as well as for those patients who received at least 80% of the duration of therapy assigned by the protocol (D).
Gastroenterology  , e5DOI: ( /j.gastro )
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4. Figure 3
Algorithm for the management of boceprevir-related anemia. This algorithm reflects the data from this clinical study, data from additional clinical studies with boceprevir in a general HCV population, and the expert opinion of the authors. Risk factors for development of anemia are low baseline hemoglobin, normal inosine triphosphate pyrophosphatase activity, age (older than 40 years), and baseline fibrosis (F3 and F4) (Table 2), and these should be considered when determining the frequency of monitoring hemoglobin. Monitoring the level of hemoglobin for anemia is focused largely on the first 12 weeks of treatment because the decline in hemoglobin stabilizes around treatment week 12 (4 weeks peginterferon/RBV + 8 weeks boceprevir/ peginterferon/RBV) (Supplementary Figure 2). All patients should receive peginterferon (1.5 μg/kg/wk)/RBV for 4 weeks, and then add boceprevir (800 mg 3 times a day). Initial dosing with RBV is based on the patient's weight: 800 mg/d for <40 to 65 kg (in this clinical study, patients weighing 40−50 kg received 600 mg/d and patients weighing 50−65 kg received 800 mg/d); 1000 mg/d for 66−80 kg; 1200 mg/d for 81−105 kg; 1400 mg/d for >105 kg. With patients who have advanced fibrosis or cirrhosis, hemoglobin levels should be checked very frequently for the first 8 weeks, and should be monitored closely at other time points as clinically appropriate. Frequent hemoglobin testing might be appropriate if a patient drops close to 10 g/dL. In contrast, the hemoglobin level in a patient without advanced fibrosis or cirrhosis should be checked every 2 weeks for the first 4 weeks, and should be monitored closely at other time points as clinically appropriate. For example, if the hemoglobin level in a patient without advanced fibrosis or cirrhosis drops to 10 g/dL by week 4, then weekly testing might be needed. Dose reduction of RBV should be the primary intervention for managing anemia. However, if the hemoglobin level remains <10 g/dL after RBV dosage reduction, the administration of EPO should be considered as well as reducing the dosage of peginterferon to 1.0 μg/kg/wk, especially if the reticulocyte counts are low. If RBV is permanently discontinued for management of anemia, then peginterferon alfa and boceprevir must also be discontinued. Once the hemoglobin level is >10 g/dL, the dosage of RBV should be increased in 200 mg/d steps to a dosage less than the initial dosage of RBV. However, the goal should be for the patient to receive at least 50% of the total milligrams of RBV calculated from the initial RBV dosage (mg/d) and the assigned duration defined by the response-guided therapy algorithm (28, 36, or 48 weeks). Once the hemoglobin level is >11 g/dL, the administration of EPO should be discontinued.
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5. Supplementary Figure 1
Study design and patient disposition. Patients (N = 1154) were assessed for eligibility. Eligible patients (n = 687) received 4 weeks of peginterferon/RBV followed by 24 or 44 weeks of boceprevir (800 mg 3 times a day) plus peginterferon/RBV. The study was projected to enroll a sample size of 660 patients to be treated with boceprevir/peginterferon/RBV. Approximately 60% (400 patients) were expected to develop anemia. The precision of the 95% CI for the true difference in SVR rates between the treatments was expected to be approximately ±10%. Patients with detectable HCV RNA (≥25 IU/mL) and a <2 log10 decline from baseline HCV RNA levels at treatment week 12 discontinued treatment, as did patients with HCV RNA ≥25 IU/mL at treatment week 24. Patients remained in the Treated/Not Randomized arm (n = 187) if their hemoglobin values remained >10 g/dL throughout the 28-week or 48-week treatment period or they discontinued treatment before randomization. Patients with hemoglobin ≤10 g/dL during the lead-in phase with peginterferon/RBV or who became anemic (hemoglobin ≤10 g/dL) during study treatment were randomized in a 1:1 ratio to RBV dosage reduction (RBV DR) or EPO use. If the rate of hemoglobin decline suggested that the value would be ≤10 g/dL before the next protocol-specified visit and the value was <11g/dL, then the patient could be randomized to RBV dosage reduction or EPO use. Patients randomized during the lead-in period with peginterferon/RBV might have delayed initiation of boceprevir for up to 2 weeks at the discretion of the investigator if the anemia was significant.
Gastroenterology  , e5DOI: ( /j.gastro )
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6. Supplementary Figure 2
Mean hemoglobin concentration (g/dL) over time by treatment arm. Mean hemoglobin concentrations by treatment arm are shown from the start of study therapy. FU, follow-up.
Gastroenterology  , e5DOI: ( /j.gastro )
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